Multiple antibiotic resistance in bacteria is a serious clinical problem. Our studies on Escherichia coli have shown that it resists a variety of antibiotics, organic solvents and superoxides by increased transcription of a set of about 40 genes called the mar/sox/rob regulon. The increased transcription can be accomplished by any one of three homologous, but separately regulated, activator proteins, MarA, SoxS or Rob. Our recent studies of the regulation of these activators has revealed a novel form of environmental cross-talk.[unreadable] [unreadable] We have previously shown that marA transcription is increased in cells exposed to salicylate (SAL) by a mechanism involving SAL binding to the MarR protein and thereby preventing it from repressing the marA promoter. We had also shown that 2,2?-dipyridyl (DIP) enhances the activity of the abundant but inactive Rob protein by binding Rob post-translationally. Others (Demple; Weiss) have shown that SoxS transcription is activated by SoxR after SoxR has been converted to an oxidized form by superoxides. We now report that SoxS expression can also be elevated by treatment of the bacteria with SAL or DIP but by mechanisms that seem unrelated to those whereby they activate MarA and Rob, respectively.[unreadable] [unreadable] Using promoters fused to lacZ, we could precisely measure the effects of SAL and DIP on transcription of the promoters even in the absence of the wild-type soxR or soxS structural gene. A small but significant activation of soxR and soxS transcription by SAL was found in cells deleted for both the mar and rob genetic systems. This effect required wild type SoxR to be present. A somewhat greater effect was seen with DIP. Since DIP is a strong chelator of Fe and since SoxR requires Fe-S clusters for repressional activity, our working hypothesis is that DIP strips SoxR of Fe thereby preventing it from autorepressing its own promoter resulting in higher transcriptional activity. A similar mechanism has been suggested for IscR, the regulator of an operon that is responsible for Fe-S cluster formation. When stripped of Fe, IscR loses its autorepressor activity and becomes an activator of other promoters. The next challenges are to understand (a) how SoxR can transcriptionally activate soxS if the normal Fe-S clusters have been altered or removed and (b) what is the evolutionary significance of environmental cross-talk of SAL and DIP with mar, sox and rob.